Appeal panel decision: Irinotecan, oxaliplatin and raltitrexed for colorectal cancer

NATIONAL INSTITUTE FOR CLINICAL EXCELLENCE
     
Appraisal of the use of irinotecan, oxaliplatin and raltitrexed drugs in the treatment of advanced colorectal cancer
     
Decision of the Appeal Panel
     
1. Introduction  
     
  1.1 The Appeal Panel convened a hearing on 23 May 2001 to consider appeals against the Institute's Guidance to the NHS on the use of irinotecan, oxaliplatin and raltitrexed in the treatment of advanced colorectal cancer ("the Guidance") as set out in the Final Appraisal Determination produced by the Appraisal Committee ("the FAD").
     
  1.2 The Appeal Panel comprised Professor Parveen Kumar (Chair of the Appeal Panel and non-executive member of the Institute's Board), Mr Roy Luff (non-executive member of the Institute's Board), Ms Mercy Jeyasingham (non-executive member of the Institute's Board), Ms Gill Donovan (patient representative) and Dr Peter Read (industry representative).
     
  1.3 Appeals were lodged by the following appellants:
     
    Aventis Pharma Limited ("Aventis");
    Sanofi-Synthelabo Limited ("Sanofi");
    AstraZeneca UK Limited ("AstraZeneca");
    United Kingdom Co-ordinating Committee on Cancer Research ("UKCCCR");
    CancerBACUP
     
    In addition, Macmillan Cancer Relief indicated that it supported the appeal lodged by CancerBACUP.
     
  1.4 The following individuals involved in the appraisal were present to answer questions from the Appeal Panel: Professor David Barnett (Chairman of the Appraisal Committee); Professor Ray Tallis (Member of the Appraisal Committee); Dr Norman Waugh (Member of the Appraisal Committee); Professor Peter Littlejohns (Executive Lead for this appraisal); Dr Sarah Garner and Dr Alec Miners (Technical Leads for this appraisal).
     
  1.5 The three grounds upon which the Appeal Panel can hear an appeal are:
     
    (1) The Institute has failed to act fairly and in accordance with the Appraisal Procedure set out in the Interim Guidance for Manufacturers and Sponsors;
     
    (2) The Institute has prepared guidance which is perverse in the light of the evidence submitted;
     
    (3) The Institute has exceeded its powers.
     
Appeal by Sanofi
     
2. The headings in italics below correspond to headings in Sanofi's appeal submission. Sanofi's appeal principally concerned the Guidance in relation to the use of oxaliplatin.
   
3. Appeal Ground One: The Institute has failed to act fairly and in accordance with the Appraisal Procedure
   
  3.1 Failure to explain clinical and cost effectiveness thresholds
     
  The Appeal Panel considered that the reasoning in the FAD was insufficient to explain the Guidance in paragraphs 1.1 and 1.2 of the FAD and that the Committee's reasoning was not transparent on the face of the FAD.
   
  The Appeal Panel therefore upheld the appeal on this ground.
   
  3.2 Failure to declare conflict of interest in relation to the involvement of Dr Ledermann, and the effect of that conflict
     
  The Appeal Panel accepted the explanation of the Appraisal Committee that Dr Ledermann's contribution to the Appraisal Committee was as an expert and not as the co-ordinator of the FOCUS trial. However the Appeal Panel can understand the appellants' concern about a potential for conflict of interest given the references to the FOCUS trial in the FAD and the fact that the minutes of the Appraisal Committee meeting on 7 February 2001 did not record a discussion of the potential conflict of interest. The Panel therefore upheld this point on the basis of a failure of "process".
   
  The Appeal Panel therefore upheld the appeal on this ground.
     
  3.3 Failure to demonstrate transparency of process by disclosing the nature of Dr Ledermann's evidence
     
  The Appeal Panel noted that the Transparency Directive requires that expert opinions be communicated "if appropriate". Given that the Appraisal Committee did not identify an actual conflict of interest in relation to Dr Ledermann's involvement in the Appraisal Process, the Appeal Panel accepts that (if the Transparency Directive applies to the Guidance) it was not necessary for the Appraisal Committee to isolate Dr Ledermann's evidence as contended by Sanofi.
   
  The appeal on this ground was not upheld.
   
4. Appeal Ground Two: The Institute has prepared guidance which is perverse in the light of the evidence submitted.
     
  4.1 Failure of the Guidance to reflect the conclusions of the Evaluation Report
     
  The Appeal Panel considered that the Appraisal Committee are not bound to follow the conclusions of the Evaluation Report. Indeed, the Appraisal Committee have a duty to consider all the evidence provided to them, and are required to draft Guidance which reflects their view of the evidence as a whole. The Panel therefore considered that the Guidance could not be considered to be perverse only on the basis that it does not endorse the conclusions of the Evaluation Report.
   
  The appeal on this ground was not upheld.
   
  4.2 Failure by the Evaluation Report and the Appraisal Committee to consider health economics data
     
  The Appeal Panel accepted the statements by the Appraisal Committee at the appeal hearing that they had fully considered the health economics evidence available to them. The Appeal Panel also accepted that the Determination could not be considered to be perverse only because the Appraisal Committee had taken a different view from that of the appellants with regard to the weight to be given to particular elements of that evidence.
   
  The appeal on this ground was not upheld.
   
  4.3 Perverse analysis of outcomes
     
  The Appeal Panel agreed that the FAD does not in itself adequately explain the Appraisal Committee's reasons for not recommending the use of combination oxaliplatin as a first-line therapy in light of the evidence referred to in paragraph 4 of the FAD. Further, in the course of the appeal hearing the Appraisal Committee was not able to show the Appeal Panel that there was a reasonable justification for the recommendation in light of the evidence.
   
  The Appeal Panel therefore upheld the appeal on this ground.
   
  4.4 Conflict between the product licence for oxaliplatin and the FAD and perverse recommendation for further trials of a product with proven and accepted effectiveness
     
  The Appeal Panel considered that the fact that a product has been licensed cannot mean that a negative recommendation by the Institute is in itself perverse. The Institute has a different function from that of the licensing authority, namely the appraisal of the clinical and cost effectiveness of products used in the NHS. However, the Appeal Panel considered that the Guidance in paragraphs 1.1 and 1.2 of the FAD is perverse because it is inconsistent with the conclusions as to the clinical effectiveness of the product which are expressed in the remainder of the FAD. At the appeal hearing the Appraisal Committee did not explain their reasoning so as to correct or account for that inconsistency.
   
  The Appeal Panel therefore upheld the appeal on this ground.
   
  4.5 Failure to identify clinical effectiveness threshold
     
  The Appeal Panel does not consider that Guidance/a FAD issued by the Institute is required to specify a level of clinical effectiveness to be met by particular products. Under Appeal Ground Two the overall requirement on the Appraisal Committee is that it produce Guidance/a Determination which is reasonable on the basis of the evidence available. The adequacy of the reasoning behind the Guidance in this case is properly dealt with under other grounds of appeal raised by Sanofi and others.
   
  The appeal on this ground was not upheld.
   
  4.6 Failure to identify cost effectiveness threshold
     
  The Appeal Panel does not consider that Guidance/a FAD issued by the Institute is required to specify a level of cost effectiveness to be met by particular products. As indicated in 4.5 above, the Panel considered that the overall requirement on the Appraisal Committee is that it produce Guidance which takes reasonable account of the evidence before the Appraisal Committee. The adequacy of the reasoning behind the Guidance in this case is properly dealt with under other grounds of appeal raised by Sanofi and others.
   
  The appeal on this ground was not upheld.
   
  4.7 Failure to make comparisons transparent
     
  The Appeal Panel were satisfied, on the basis of statements from the Committee's members, that the Appraisal Committee considered the full range of evidence available to it. However, it agrees that the reasoning in relation to that evidence is not apparent in the FAD and they were unable to determine a reasonable basis for the Committee's determination either from the FAD itself or from the statements of the Appraisal Committee at the appeal hearing.
   
  The Appeal Panel therefore upheld the appeal on this ground.
   
  4.8 Perverse interpretation of the likely outcome of the FOCUS trial
     
  The Appeal Panel agreed that the FOCUS trial will not provide the further evidence which the Appraisal Committee appeared to consider it should have before making a recommendation for use of the products under appraisal. The Appeal Panel also noted that the results of that trial will not be available for some time. The Appeal Panel therefore concluded that it was perverse for the Appraisal Committee to have recommended involvement in, and reliance on, the outcome of the FOCUS trial. The Appraisal Committee should have given guidance on the circumstances in which the products could be used prior to the outcome of further trials.
   
  The Appeal Panel therefore upheld the appeal on this ground.
   
  4.9 Perverse enshrinement of inequality
     
  The Appeal Panel considered that it was not necessary or appropriate for them to consider a ground of appeal based on the effect of the Guidance and framed as a reference to inequality in light of the findings they had already made regarding the perversity of the Guidance in itself.
   
  The appeal on this ground was not upheld
   
4.10 Perverse consideration of clinical response data
     
  The Appeal Panel agreed that the Guidance is inconsistent with the data which shows that significantly more patients may respond to the combination treatment than to 5FU/FA alone and the evidence regarding use of the combination treatment to reduce tumour volume to enable curative surgery. They did not obtain from the Appraisal Committee a satisfactory explanation of that apparent inconsistency to indicate the existence of a reasoned basis for the Guidance in paragraphs 1.1 and 1.2 of the FAD.
   
  The Appeal Panel therefore upheld the appeal on this ground.
   
  4.11 Perverse rejection of outcome data
     
  The Panel considered that the Licensing Authority's view of data before the Appraisal Committee is not relevant to its consideration of the Guidance, as indicated in paragraph 4.4 above. However, the Appeal Panel agreed that the Guidance appears to be inconsistent with the outcome data and considered that the inconsistency was not explained by the Appraisal Committee.
   
  The Appeal Panel therefore upheld the appeal on this ground.
   
  4.12 Perverse disregard for ethical considerations
     
  The Appeal Panel agreed that in this particular case the recommendation that the drug be available only within clinical trials was inconsistent with ethical requirements for clinicians, and the Appraisal Committee were not able to satisfy them that there was a reasonable basis for the recommendation.
   
  In that regard, the Appeal Panel noted the statement by Professor Barnett that the Committee recognised that randomisation would be impossible in certain contexts given the nature of the patient groups using the products under appraisal. Professor Barnett conceded that paragraph 1.2 of the Guidance should perhaps have been worded so as to read:
   
  "Combinations of irinotecan or oxaliplatin with 5FU/FA therapy are recommended for first-line neoadjuvant therapy…only within recognised cancer centres".
   
  The Appeal Panel therefore upheld the appeal on this ground.
   
Appeal by Aventis
     
5. The headings in italics below correspond to the headings in Aventis' appeal submission. Aventis' submissions were principally concerned with the recommendations in the guidance regarding the use of irinotecan.
     
6. Appeal Ground One: The Institute has failed to act fairly and in accordance with the Appraisal Procedure
     
  6.1 Failure to disclose the pharmacoeconomic model relied on by the Appraisal Committee
     
  The Appeal Panel are satisfied that the Appraisal Committee considered a wide variety of pharmacoeconomic models and followed the Institute's published procedures in carrying out consultation with Aventis. However, in view of the large cost discrepancy between Aventis' model and the Institute's figures and the importance of this issue to the appraisal as indicated by Aventis in its requests for disclosure, the Panel felt that it was unfair that the information had not been shared in this particular instance.
   
  The Appeal Panel therefore upheld the appeal on this ground.
   
  6.2 Partiality with regard to the FOCUS trial
     
  The Appeal Panel has dealt with this point under paragraph 3.2 above.
     
7. Appeal Ground Two: The Institute has prepared guidance which is perverse in the light of the evidence submitted.
     
  7.1 Conclusions challenged: perversity of determination in relation to first-line use of combination therapies in light of the evidence in paragraph 4 of the FAD
     
  The Appeal Panel agreed that the Guidance in paragraphs 1.1 and 1.2 of the FAD appeared to be inconsistent with the evidence contained in paragraph 4 and considered that the Appraisal Committee did not provide an explanation of its reasoning which resolved the inconsistency.
   
  The Appeal Panel therefore upheld the appeal on this ground.
     
  7.2 Toxicity and cost-effectiveness
     
  The Appeal Panel noted that Aventis' submissions on these points were put forward to show that the Guidance was perverse if it was based on either of these two factors. As the Appraisal Committee did not indicate that it had based its determination specifically on one or both of these two factors, and as the Appeal Panel has upheld the appeal points in paragraph 4.3, 4.4 and 4.10 above with regard to the perversity of the Guidance in light of the totality of the evidence before the Appraisal Committee, the Panel did not consider it necessary or appropriate to make findings on these two grounds.
   
  7.3 Recommendations as to further research
     
  This ground of appeal is upheld on the basis set out in paragraphs 4.8 and 4.12 above.
     
Appeal by UKCCCR
     
8. Appeal Ground Two: The Institute has prepared guidance which is perverse in the light of the evidence submitted.
     
  UKCCCR set out two broad grounds of appeal.
     
  8.1 Perversity of the guidance in relation to first line combination chemotherapy for inoperable liver metastases where a response to chemotherapy will result in a chance of curative surgery
     
  The Appeal Panel agreed that the Guidance in paragraphs 1.1 and 1.2 appeared to be inconsistent with the evidence referred to in paragraph 4 of the FAD and with the matters set out in UKCCCR's submission. The Panel considered that the Appraisal Committee did not provide a response to this apparent inconsistency which indicated that there was a reasonable basis for the Guidance.
   
  The Appeal Panel therefore upheld the appeal on this ground.
   
  8.2 Perversity in relation to use of irinotecan and oxaliplatin as second line therapies
     
  The Appeal Panel again noted that the Appraisal Committee had not, either in the FAD or in the course of the appeal hearing, set out a reasonable basis for the Guidance in this regard in light of the evidence which was available to it and which is summarised in paragraph 4 of the FAD.
   
  The Appeal Panel therefore upheld the appeal on this ground.
   
Appeal by CancerBACUP
     
9. Appeal Ground Two: The Institute has prepared guidance which is perverse in the light of the evidence submitted.
     
  9.1 CancerBACUP submitted that the determination excluding combination therapies from the first line treatment of patients whose liver metastases may become operable is perverse on the basis of the evidence which is available to show the effect of combination therapies on these patients. CancerBACUP expressed the view that where a treatment offers a potential for cure in an otherwise incurable situation, that treatment should not be refused because data from randomised trials is not available. CancerBACUP also referred to the fact that the cost implications of recommending combination therapy would not be significant.
     
  For the reasons already set out in this decision the Appeal Panel agreed that the Guidance in paragraphs 1.1 and 1.2 of the FAD is perverse in light of the evidence available to the Appraisal Committee.
   
  The Appeal Panel therefore upheld the appeal by CancerBACUP.
   
Appeal by AstraZeneca
     
10. The headings in italics below correspond to the paragraphs numbered 1.2-1.2 and 2.1 - 2.5 in AstraZeneca's appeal submission. That submission was concerned with the Guidance in paragraph 1.4 of the FAD regarding the use of raltitrexed.
     
11. Appeal Ground One: The Institute has failed to act fairly and in accordance with the Appraisal Procedure
     
  11.1 Decision by the Assessment Group regarding the value of clinical data leading to failure to undertake cost effectiveness calculations
     
  The Appeal Panel noted the statement by Professor Barnett that the Appraisal Committee would have requested cost effectiveness calculations if it had considered them necessary, and accepted the Appraisal Committee's general statement that they had reached their own decision on clinical and cost effectiveness on the basis of all the evidence presented to them.
   
  The appeal on this ground was not upheld.
   
  11.2 There was insufficient data available to the Appraisal Committee to enable it to properly evaluate the cost effectiveness of raltitrexed
     
  The Appeal Panel was satisfied that the Appraisal Committee used its discretion reasonably in determining the amount of cost effectiveness data it required to reach its decision.
   
  The appeal on this ground was not upheld.
   
12. Appeal Ground Two: The Institute has prepared guidance which is perverse in the light of the evidence submitted.
     
  12.1 Failure to take account of the nature of the patient population eligible for raltitrexed
     
  The Appeal Panel accepted that the Appraisal Committee's statement that they were well aware of the nature of this patient group.
   
  The appeal on this ground was not upheld.
   
  12.2 Failure to reflect patients' perspective and objectives of treatment in the guidance
     
  The Appeal Panel agreed that paragraph 1.4 of the determination appeared to be perverse in view of the nature of the patient group for which raltitrexed is used and did not consider that the Appraisal Committee produced a reasonable basis for that determination in the course of the appeal hearing.
   
  The Appeal Panel therefore upheld the appeal on this ground.
   
  12.3 The data about raltitrexed which is presented in the FAD incorrectly represents the results of the clinical trials
     
  The Appeal Panel did not consider that it was in a position to comment on the figures in the FAD, and considered that it was not necessary for it to do so in light of its other findings in relation to perversity.
   
  The appeal on this ground was not upheld.
   
  12.4 The FAD fails to focus on mature endpoint clinical trial data
     
  The Appeal Panel noted that this submission differed from that made by Sanofi in relation to consideration of outcome data, in that it concentrated on the alleged confusion resulting from a reference to two types of endpoint. The Appeal Panel considered that such potential confusion was not in itself a matter going to perversity of the determination and that any substantive issues which lay behind this submission would in any event be dealt with by the Appeal Panel's finding under paragraph 12.2 above.
   
  The appeal on this ground was not upheld.
   
  12.5 The FAD fails to take into account the cost effectiveness data for raltitrexed for the reasons set out in grounds 11.1 and 11.2 above.
     
  The Appeal Panel refer to their decision in relation to paragraphs 11.1 and 11.2 and paragraph 12.2 above. The Panel consider that this ground does not constitute a separate ground of perversity which it needs to consider.
     
Appeals by Sanofi, Aventis and AstraZeneca
     
13. Appeal Ground Three: The Institute has exceeded its powers
     
  These appellants made a number of submissions under this ground relating to the alleged status of the guidance as a de facto ban and alleged contraventions of the Transparency Directive. The Appeal Panel was grateful for the succinct presentations made to them in relation to this ground. However, the Appeal Panel have already determined that the Appraisal Committee have not shown that there was a reasoned basis for their determinations, with the result that the determination is to be remitted back to the Appraisal Committee for further consideration. The Appeal Panel therefore considers it is not necessary to determine either the applicability of the Transparency Directive to this appraisal or the other points made under this ground.
     
The Appeal
   
14. The Appeal Panel upholds the appeal having found in favour of the appellants on a number of points under Ground One and Ground Two.
   
15. The Appraisal should now be referred back to the Appraisal Committee for reconsideration in light of the Appeal Panel's findings and such new evidence relevant to the appraisals as the consultees are now able to provide.
   
16. The Appeal Panel wishes to say that it was conscious of the vast amount of work carried out by the Appraisal Committee. However, the Appeal Panel was generally concerned about the ambiguity of the language in the FAD and the lack of clarity as to the nature of the reasoning behind the Guidance. The Panel recommends that the Committee take particular care in wording the new FAD to ensure that the Guidance and the reasoning behind it can be clearly understood by all readers.
   
17. The Appeal Panel noted that a great number of experts were present at the appeal hearing, but it was pointed out to the Panel that this range of expertise had not been available to the Appraisal Committee during the appraisal process. Some of the appellants indicated that they had not noticed the request for nomination of experts within the initial correspondence from the Institute regarding the appraisal. The Appeal Panel recommends that when letters are sent to prospective consultees among Professional and patient Groups, the requests in those letters for nominations of experts to attend meetings of the Appraisal Committee be highlighted sufficiently to ensure that readers of the letter are aware of their ability to make nominations.

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Copyright 2014 National Institute for Health and Care Excellence. All rights reserved.

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Copyright 2014 National Institute for Health and Care Excellence. All rights reserved.